Affective disorders (anxiety and depression) are the most common psychiatric disorders in the general population (Alonso et al, 2004a; Kessler et al., 2005), considering that approximately 35% of women and 20% of men will present one or the other of these conditions at least once during their life. In the absence of care, they are generally in the form of episodes lasting over at least several months and that may repeat over life. Their impact is variable depending on their severity, but on average it appears as very significant, especially in the professional and social fields (Alonso et al, 2004b; Greden et al., 2001), due to direct medical and medical-social expenses and indirect expenses incurred by work absenteeism. The annual cost of depression in the US is close to that of cardiovascular diseases and is estimated at $44 billion of which nearly 12% are attributable to hospitalizations (Greenberg et al, 1993). In Europe, data is difficult to gather but some studies suggest direct cost per patient of up to  14,500 and indirect costs of approximately  4,500, for a total of just over 105 million euros (Andlin-Sopcki & Wittchen, 2005). Depressive illnesses, which often affect young and working populations, also have a significant economic impact on “indirect costs” measured in terms of productivity for the individual and for society (Druss et al, 2000).
There are well validated first-line therapeutic strategies (in general drug and/or psychosocial) for most categories of depressive disorders (DDs), that can effectively treat more than half of patients.
However, if the majority of depressive episodes regress during a first treatment, it is generally accepted that 20% of depressive episodes become chronic and that 30% of all depressions are resistant to conventional antidepressant drugs (Fava and Davidson, 1996). Patients with such treatment-resistant depression (TRD) may maintain intense symptoms for several months or years despite the use of many treatments. There are currently no precise and consensual recommendations for the monitoring and evaluation of patients showing failure to a first antidepressant treatment and a resistant form of depression. In general, practitioners test different classes of antidepressants, combination therapies or the use of other therapeutic methods such as electroconvulsive therapy (ECT) in severe and resistant depressions (Little 2009; Trivedi et al, 2006). While different types of algorithms have been proposed to guide the selection of treatment strategies based on initial responses and have shown some improvement in the efficiency of treatment (Trivedi et al, 2004), there is still a need for true therapies for those depressive patients resistant to conventional antidepressant drugs. This is particularly true because it has been demonstrated that the probability of response to a drug treatment (n=i) decreases significantly depending on the number of drugs tested before (n=2, n=3). Thus, after at least three or four drug trials, the probability of response to the drug is very low (<15%) and the use of other therapeutic options with different biological effects (physical treatments such as ECT therapy) is necessary (Rush et al., 2009).
Presently, treatments that have been found really efficient in treatment-resistant depression are either highly invasive or based on chemical drugs with significant secondary effects:                Electroconvulsive therapy (ECT) has been shown to be efficient in the treatment of treatment-resistant depression (TRD).        However, ECT involves intentionally triggering a brief seizure by passing small electric currents through the brain, under general anesthesia, and it thus a quite invasive procedure that necessitates hospitalization of the patient and high medical skills. In addition, ECT is not devoid of side effects, such as confusion, short-term or sometimes long-term memory losses, nausea, headache, jaw pain or muscle ache. Moreover, during ECT, heart rate and blood pressure increase and this treatment may not be recommended in people with unstable heart problems.        Ketamine has been reported to exert a rapid antidepressant-like efficacy (Scheuing et al., 2015). In particular, ketamine has been shown to decrease immobility in the forced-swimming test (FST) the Wistar Kyoto rat strain (WKY) (Tizabi et al., 2012) and to decrease explicit suicidal ideation in human TRD patients (Scheuing et al., 2015).        However, ketamine is also known to temporarily cause dissociative symptoms, to have risk for abuse, and to increase oxidative stress in the rat brain. Moreover, while ketamine rapidly reduces depressive symptoms, repeated infusions are necessary to maintain its effects over time, the effects of a single infusion only lasting about 1 week. Such repeated infusions may lead to serious side effects, such as cognitive impairments, psychomimetic symptoms, and schizophrenia-like behaviors (Scheuing et al., 2015).        Despite its efficiency in alleviating depressive symptoms in TRD, ketamine cannot thus be widely used in the treatment of TRD.        
From the above, it appears that the only treatments available at this stage for the treatment of TRD are not satisfactory, since they are either quite invasive or prone to significant side effects. New treatments of TRD, that would not have these drawbacks, but would instead be non-invasive and well tolerated, without significant side effects, are thus needed.
It has been shown that stress is involved in the onset of depression, primarily by damaging the hippocampus, and most antidepressant drugs have been obtained based on stress-related animal models of depressive disorders and found to have the common mechanism of action of reversing the neurotoxic effects of stress and repairing the damaged hippocampus (Willner & Belzung, 2015).
It is thus not surprising that most antidepressant drugs are not efficient in depressive disorders in which stress is not the main factor involved in the pathology. Indeed, many factors are known to increase vulnerability to depression, including a clinical history of depression and a variety of genetic, personality or developmental risk factors. When such factors are present, the role of stress in depression is correspondingly diminished and the major substrate for most antidepressant action (stress-induced neurotoxicity) is absent or minor. In this context, it should be noted that increased vulnerability to depression has been shown to be associated with resistance to antidepressant drug treatment (Willne et al. 2014).
In fact, treatment-resistant depression appears to be associated to risk factors for depression, which predispose to the precipitation of depressive episodes by relatively low levels of stress.
The above clearly shows that while stress-related animal models of depressive disorders are useful for predict therapeutic efficiency of a compound in depressive disorders precipitated by stress (the most common form of depressive disorder), they are not appropriate to predict therapeutic efficiency of a compound in the treatment of treatment-resistant depression. In this respect, it should be noted that most antidepressant drugs, including SSRIs, have been screened using such stress-related animal models of depressive disorders and were thus found to be efficient in these models. This however did not prevent them to be inefficient in many cases of treatment-resistant depression.
Instead, only animal models that incorporate predisposing factors leading to heightened stress responsiveness may be used for predicting therapeutic efficiency of a compound in the treatment of treatment-resistant depression (TRD). Such models include those proposed in Willner & Belzung, 2015, the 5 better models for this purpose being considered to be the Wistar-Kyoto (WKY) and congenital learned helplessness (cLH) rat strains, the high anxiety behaviour (HAB) mouse strain and the CB1 receptor knockout and OCT2 null mutant mouse strains. These animal models have been shown to display at least some resistance to some conventional antidepressant drugs found inefficient for the treatment of TRD in a clinical setting. For instance, WKY rats have been found to be resistant to acute or chronic administration of fluoxetine (an SSRI, see Durand et al., 1999; Griebel et al., 1999; Lopez-Rubalcava and Lucki, 2000), acute administration of citalopram (another SSRI, see Pollier et al., 2000), as well as for sub-chronic administration (12 days) of paroxetine (a third SSRI, see Tejani-Butt et al., 2003), and may thus be used as an animal model of TRD.
3β-methoxy-pregna-5α-ene-20α-one (also referred to as 3β-methoxy-pregnenolone or 3β-methoxy-PREG) is a synthetic derivative of pregnenolone (3β-hydroxypregn-5α-en-20α-one), the natural precursor of steroid hormones, and in particular of neurosteroids. The 3β-methoxy function of 3β-methoxy-PREG prevents its conversion to its neuroactive metabolites. 3β-methoxy-PREG is believed to modulate the microtubule through its binding at microtubule-associated protein2 (MAP2) (Fontaine-Lenoir et al., 2006; Murakami et al., 2000). 3β-methoxy-PREG may therefore stimulate neuronal plasticity, as shown by its efficacy to enhance neurite extension of PC12 cells (Fontaine-Lenoir et al., 2006).
It has been shown that 3β-methoxy-PREG shows rapid and persistent antidepressant-like properties in stress-related animal models of depressive disorders:                U.S. Pat. No. 8,334,278 shows that 3β-methoxy-PREG:                    decreases immobility of naïve adult male Sprague Dawley rats in the forced swimming test (FST), similarly to fluoxetine (an SSRI).            increases memory retention in naïve adult male Sprague Dawley rats in the Novel object recognition test (NOR), and            induces recovery of memory deficit in the NOR test in social-isolated adult male Sprague Dawley rats. Social-isolated adult male Sprague Dawley rats were obtained by rearing them in isolation from the time of weaning and throughout adulthood. This social isolation protocol creates a stress that induces a series of hippocampal structural and molecular deficits paralleled by behavioural alterations resembling a stress-induced depressive-like state (Weiss and Feldon, Psychopharmacology 2001; Bianchi et al., EJN 2006).                        Bianchi and Baulieu, 2012 presents the same data as U.S. Pat. No. 8,334,278 and additionally shows that 3β-methoxy-PREG:                    decreased immobility of social-isolated adult male Sprague Dawley rats in the forced swimming test (FST), similarly to although more rapidly than fluoxetine (an SSRI), and            recovered increased anxiety of social-isolated adult male Sprague Dawley rats in the subchronic phase (8 days of daily injections) but not in the acute phase (2 days of daily injections) in the Elevated plus maze (EPM) test, similarly to although more efficiently than fluoxetine.                        Paresys et al., 2015 tested 3β-methoxy-PREG in tree shrews exposed to chronic psychosocial stress.        The tree shrew (Tupaia belangeri) is a day-active animal phylogenetically close to primates. Prolonged psychosocial stress was created in male tree shrews by a recurrent introduction of one male into the territory of another male to develop a dominant/subordinate relationship. The biobehavioral responses observed in subordinate tree shrews are similar to the symptoms observed in depressed patients. In this model, stress-induced alterations include social avoidance, cortisol and noradrenaline increase, elevation of core body temperature and sleep disturbances.        A 4-week daily administration of 3β-methoxy-PREG was found to abolish stress-triggered avoidance behavior and to prevent hormone hypersecretion, hypothermia and sleep disturbances, in a manner similar to fluoxetine (an SSRI).        
Based on the above finding, 3β-methoxy-PREG has thus already been proposed for the treatment of depressive disorders.
However, as clearly appears above, animal models used in U.S. Pat. No. 8,334,278, in Bianchi and Baulieu, 2012 and in Paresys et al., 2015 are stress-related animal models of depressive disorders, in which depressive symptoms or behaviors are created by imposing acute or chronic stress to the animals.
As explained above, such stress-related animal models of depressive disorders are not suitable for predicting therapeutic efficiency on TRD, since TRD is associated to the presence of risk factors for depression, which predispose to the precipitation of depressive episodes by relatively low levels of stress. This is for instance illustrated by the fact that in all these data, the action of 3β-methoxy-PREG was similar to, although sometimes more rapid or more pronounced than fluoxetine, an SSRI antidepressant known to be inefficient in the treatment of TRD.
Data available for 3β-methoxy-PREG thus supported the use of this compound in the treatment of conventional depressive disorders, which may be treated by other antidepressant drugs such as SSRIs, but not of TRD, in which SSRIs are known to be generally inefficient.